Refactoring biosynthetic gene clusters for heterologous production of microbial natural products

Microbial natural products (NPs) are of paramount importance in human medicine, animal health and plant crop protection. Large-scale microbial genome and metagenomic mining has revealed tremendous biosynthetic potential to produce new NPs. However a majority of NP biosynthetic gene clusters (BGCs) are functionally inaccessible under standard laboratory conditions. BGC refactoring and heterologous expression provide a promising synthetic biology approach to NP discovery, yield optimization and combinatorial biosynthesis studies. In this review, we summarize the recent advances pertaining to the heterologous production of bacterial and fungal NPs, with an emphasis on next-generation transcriptional regulatory modules, novel BGC refactoring techniques and optimized heterologous hosts.